This invention relates to carbocyclic analogs of 2-amino-6-substituted-purine ribofuranosides and 2-amino-6-substituted-8-azapurine ribofuranosides. This invention also relates to the use of such compounds in the treatment of viral infections.
The term "carbocyclic analog of a nucleoside" designates a compound that has the same chemical structure as the nucleoside except that the oxygen atom of the furanose moiety of the nucleoside is replaced by a methylene group in the carbocyclic analog; or, differently expressed, in the carbocyclic analog a cyclopentane ring replaces the tetrahydrofuran ring of the analogous nucleoside. Such nucleoside analogs were designated carbocyclic analogs of nucleosides by Shealy and Clayton, Journal of the American Chemical Society, Volume 88, pages 3885-3887, 1966. The natural nucleosides and many of their true nucleoside analogs are subject to the action of enzymes (phosphorylases and hydrolases) that cleave the nucleosides to the pentose and purine or pyrimidine moieties. The biological effects of such true nucleoside analogs may be lessened by the action of these degradative enzymes. In contrast, carbocyclic analogs of nucleosides do not possess the glycosidic bond present in the true nucleosides and, therefore, are not subject to the action of these degradative enzymes. They may also be more selective in their biological actions.
The synthesis of the carbocyclic analog of guanosine (Formula II with Y=O) was reported earlier by Y. F. Shealy and J. D. Clayton in the Journal of Pharmaceutical Sciences, Volume 62, pages 1432-1434, 1973. The carbocyclic analog of guanosine is a carbocyclic analog of a ribofuranoside of a 2-amino-6-substituted-purine. The carbocyclic analogs of 8-azaguanosine (Formula IV with Y=O) and of 2-amino-6-chloro-8-azapurine ribofuranoside (Formula III with X=Cl) were reported in the same article in the Journal of Pharmaceutical Sciences. These two compounds are carbocyclic analogs of ribofuranosides of 2-amino-6-substituted-8-azapurines. The preparation in situ and the use of the carbocyclic analog (Formula I with X=Cl; Example 1) of 2-amino-6-chloropurine ribofuranoside as an intermediate were reported by Shealy and Clayton (loc. cit.), but the preparation of a pure specimen has not been reported. The carbocyclic analogs of three arabinofuranosides of 2-amino-6-substituted-purines and of three arabinofuranosides of 2-amino-6-substituted-8-azapurines were reported by H. Lee and R. Vince (Journal of Pharmaceutical Sciences, Volume 69, pages 1019-1021, 1980). These arabinofuranoside analogs either were not active against type 1 herpes simplex virus or were much less active than are the corresponding ribofuranoside analogs of this invention. The compounds of this invention differ in structure from the arabinofuranoside analogs of Lee and Vince. In the ribofuranoside analogs of this invention, the two secondary hydroxyl groups attached to the cyclopentane ring are cis to each other, whereas they are trans to each other in the arabinofuranosides.